BRPI0614057A2 - 3- (2- (dimethylamino) methyl- (cyclohex-1-yl)) -phenol maleate and its crystalline forms - Google Patents

Abstract

3- (2- (DIMETHYLAMINO) METHYL- (CYCLOHEX-1-IL)) - PHENOL-MALEATE AND ITS CRYSTALLINE FORMS. Compound 3 - [- 2- (dimethylamino) methyl (cyclohex-1-yl)] phenol maleate is a very good analgesic with effects. Crystalline form A has shown great stability both chemically and physically and is especially suitable for making active ingredients and pharmaceutical compositions.

Description

"3- (2- (DIMETHYLAMINO) METHYL- (ClCLOHEX-1 -IL)) - PHENOL-MALEATE AND ITS

CRYSTALLINE FORMS ".

The present invention relates to maleic acid salts and 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol, preferably in a 1: 1 composition, to stable crystalline salt forms. in addition to procedures for their preparation, a pharmaceutical composition containing them and the use of salt as a pharmaceutical active ingredient in a composition.

Background of the invention

EP-A1-0 753 506 describes compounds 3- [2-

(dimethylamino) methyl- (cyclohex-1-yl)] -phenols which has an analgesic effect. In the quoted

It is also mentioned in the text that it is also possible to prepare salts from the free bases,

among which maleic acid is not mentioned as a possible anion. We

examples are prepared exclusively hydrochlorides, ie a salt with an anion

monovalent. EP-A1-0 753 506 does not contain any indication regarding the

stoichiometry may be together 3- [2- (dimethylamino) methyl

(cyclohex-1-yl)] - phenols with bivalent anions, for example as hemi

1: 1 preparation. Further investigation of the compound [[2- (dimethylamino) methyl]

(cyclohex-1-yl)] phenol hydrochloride has resulted in this solid

crystalline is characterized by a marked polymorphism that produces various forms

crystal clear and also metastable. Additionally, this hydrochloride has a

strong tendency to form hydrates and solvates, which consists of a considerable

inconvenient in the case of a preparation directed to a specific crystalline form.

On the other hand, 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] -phenol-crystalline compound

hydrochloride has been shown to be clearly hygroscopic. This property profile

3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] -phenol-clear hydrochloride compound which becomes very difficult to prepare with this active substance reproducible pharmaceutical compositions which are also maintained for a period of storage. Achieving these objectives would require at least complex protective measures.

However it was surprisingly found that 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol compound with maleic acid forms a maleate in the form of a crystalline solid, preferably in a composition in proportion 1. : 1 of maleic anionic acid and 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol. Furthermore, it was surprisingly found that maleate is not hygroscopic, stable in contact with air and does not form hydrates or solvates. Furthermore, it has also been surprisingly found that 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate is only capable of forming few crystalline forms, in particular, two crystalline forms, stable at low or high temperature, and the metastable forms which can be found convert to Form A, which is stable at room temperature. Form B stable at a higher temperature may also be converted to Form A, where at low temperature both forms may be present in mixtures. Crystalline Form A is also characterized by high chemical stability at temperatures below 100 ° C. In addition, 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate also has valuable biological properties, such as good solubility, especially in polar and protic solvents, including water, and good bioavailability. The 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate compound, thanks to its proprietary profile, is extraordinarily suitable for formulating pharmaceutical compositions. A first object of the invention are maleic acid salts with 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] -phenol, where 3- [2- (dimethylamino) methyl-2-methylamide is preferred. (cyclohex-1-yl)] phenol maleate of formula (I).

The compounds according to the invention, such as the compounds of formula (I) 1 contain at positions 1 and 2 of the cyclohexane ring each chiral C atom. The compounds of the invention, such as the compounds of formula (I) 1 comprise all stereoisomers and mixtures of stereoisomers. Diastereoisomers or mixtures of diastereomeric enantiomers with a phenyl ring transfiguration and dimethyl-aminomethyl group (1R, 2R- or 1S, 2S configuration) are preferred, with the enantiomer with the configuration preferably being preferred.

absolute (1R, 2R).

The following is the structure of the 3- [2- (dimethylamino) methyl (cyclohex-1-yl)] phenol enantiomer (1R, 2R):

(THE

The compounds of formula (I) may be prepared, analogously to the procedure described in EP-A1 0 753 506 for the preparation of salts, from the free base and reaction with maleic acid or acid anhydride. maleic in the presence of water. Thus, for example, the free base 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol may be isolated from the hydrochloride described in examples 9 and EP-A1 0 753 506. For this purpose the hydrochloride is dissolved in an organic solvent, treated with an aqueous inorganic base, eg alkali metal bases or also alkali metal acid carbonates (such as LiOH, NaOH, KOH, NaHCO3, KHCO3) and separated. from the organic phase. The organic phase may be dried by isolating the base in the usual manner or optionally after concentration by evaporation of the solvent for direct salt formation.

It has surprisingly been found that salt formation leads to a crystalline form when temperature is controlled and temperatures are not applied.

above 100 ° C.

Another object of the invention is a procedure for preparing 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate of formula (I), which comprises the combination of 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol and maleic acid, where preferably at least one of the compounds is present in the form of

dissolution or suspended.

Another object of the invention is a procedure for preparing 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate of formula (I) which comprises the steps of:

(a) dissolving or suspending 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol in a solvent,

(b) mixing the solution or suspension with maleic acid or a maleic acid solution, and> 5/57 λ ^

c) isolating the compound of formula (I), where preferably at no stage

process temperature is greater than 100 ° C, and steps (a) and

(b) may also interchange.

Preferably the temperature does not exceed 80 ° C, preferably does not exceed 70 ° C and especially not above 60 ° C. Generally, the temperature during dissolution according to step (a) of the procedure is higher than during mixing (b).

The free base and maleic acid may be applied at a 1: 1 molar ratio, and an excess of maleic acid may also be applied, for example according to a molar ratio of up to 1.3, preferably up to 1.1.

Employing an excess of the free base does not form hemi-maleates, it even adjusts to a base molar to maleic acid ratio of 2: 1.

The amount of 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol compound present in the solution may be, for example, from 5 to 70 wt.%, Preferably up to 60 wt.%, Even preferably. 10 to 50 wt%, and in particular preferably 15 to 40 wt%, referring to the solution.

The solution of 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol may be heated and optionally cooled to the temperature required for mixing with maleic acid.

In the procedure described herein for preparing 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate, in each case maleic acid may be employed as its anhydride.

Inert (compatible) solvents for 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] -phenol and maleic acid or maleic anhydride are, for example, <246/57>.

aliphatic, cyclophatic and aromatic hydrocarbons (hexane, heptane, petroleum ether, cyclohexane, methyl cyclohexane, benzene, toluene, xylene), aliphatic halogenated hydrocarbons (methylene chloride, chloroform, do- and tetrachlorethane), nitrile (acetonitrile , propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether, t-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dicetylene glycol dimethyl ether), ketones (acetone, 2-butanes ethoxy ketones, methyl isobutyl acids, carboxyether Iactones (methyl or ethyl ester of acetic acid, valerolactone), N-substituted lactams, (N-methylpyrrolidone), carboxylic acid amides (dimethyl acetamide, dimethylformamide), acyclic or non-cyclic ureas (dimethylimidazoline) and sulfoxides and suiphones (dimethylsulfoxides) dimethylsulfone, tetramethylene sulfoxide, tetramethylene sulfone) and alcohols (methanol, ethanol, 1-O 2-propanol, n-, i-, t-buta nol, 1-pentanol, 1-hexanol, 1-hexanol, 1-octanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethyl glycol monomethyl ether or omonoethyl ether and water. The solvents may be employed alone or in mixtures of at least two solvents. Advantageously, physiologically acceptable solvents are used which are known to the person skilled in the art.

Mixing in process step (b) can be accomplished by slowly or rapidly incorporating one solution into another solution. One or both hiccups may have warmed up. However, mixing may also take place such that one or both solutions are at room temperature or have cooled, for example to (-) 20 ° C and preferably (-) 10 ° C. to (+) 10 ° C, especially (-) 5 to (+) 5 ° C. Once mixed, it may heat up and cool again and may continue to stir for a specified period of time. Crystal formation can also be favored by sowing or inoculating

crystals

Generally during the mixing phase a white precipitate forms which crystallizes and can be easily filtered. Isolation of the precipitate may be by decantation, filtration or centrifugation. Then the crystalline residue may be dried, for example by heating, vacuum drying or heating under vacuum or with an optionally heated inert gas stream (air, nitrogen, noble gases). The compounds of formula (I) are obtained in high yields and in high purity. Generally only a few steps are required or no additional purification steps are required, such as by recintalization, and the product may be used directly in the manufacture of the

pharmaceutical compositions.

Another object of the present invention is a maleic acid salt and the compound

3- [2- (dimethylamino) methylcyclohex-1-yl)] phenol preforming a salt of formula (I) obtained by one of the foregoing procedures. The compounds of formula (I) and the preparation procedure of the invention

have in comparison with the corresponding considerable hydrochlorides and in part more unexpected advantages. Because it is not possible to characterize hydrates and solvents, the choice of solvents to be applied is wide and not critical. Stability in contact with air and humidity allows open handling without the need to measure special protectors. The spontaneous salt formation and the formation of crystalline precipitates, as well as their good filtering capacity, allow the development of industrial scale procedures. The compounds of formula (I) are obtained according to the present invention from salt formation as crystalline solid bodies, mostly in a polymorphic form, which will be referred to below as Form A. The amorphous forms 8/57 of the compounds of formula (I) can be readily obtained, for example, by lyophilisate or by rapidly cooling the solutions. The amorphous compounds of formula (I) are not very stable and in the presence of moisture tend to crystallize. They are therefore particularly suitable as a starting material for the directed preparation of crystalline forms.

The compounds of formula (I) as crystalline solid bodies have been found to form polymorphs which may be prepared from 3- [2- (dimethylamino) methylcyclohex-1-yl)] phenol maleate and Based on their stability they are particularly suitable as active principle for the formation of pharmaceutical compositions. It is known (see, for example, the publication of Z. Jane Li and colleagues in J.Pharm.Sci., Vol. 88 (3), pages 337 to 346 (1999)) that enantiomers deliver X-ray diffractograms and spectra. Raman identical, and thus results in the same polymorphic forms. In the context of the present invention thus are understood the polymorph forms of all enantiomers.

Another object of the invention is a crystalline form of the compound 3- [2- (dimethylamino) methylcyclohex-1-yl)] phenol maleate of formula (I), which presents an X-ray diffraction diagram on the order of 20 °. up to 35 ° 2Θ, with prominent characteristic lines expressed as "d" indices (Ángstrom): 9,4 (vs), 6,8 (m), 5,56 (s), 5,30 (s), 5, 22 (s), 4.71 (s), 4.66 (s), 4.24 (m), 4.12 (m),

4.03 (m), 3.98 (s) 3.76 (m), 3.27 (m) hereinafter referred to as Form A.

In the previous and following text, the following meanings of expressions in parentheses are used: (vs) = very strong intensity, (s) = strong intensity, (m) = medium intensity, (w) = weak intensity and (vw) = Very low intensity. \ 9/57

Another object of the invention is a crystalline form A of the compound 3- [2- (dimethylamino) methyl- (cyclohex-1-yl) henol maleate of formula (I), which presents a characteristic X-ray dysfunctional diagram with the following reflexes or

pronounced reflections:

2 Theta Relative intensity 9.38 100 9.94 5 10.35 8 12.76 6 13.07 20 13.49 7 15.94 43 16.72 52 16.98 40 17.54 15 18.86 61 19, 04 48 19.28 8 20.01 5 20.57 6 20.96 24 21.57 23 22.03 20 22.33 30 23.69 15 24.84 8 25.01 9 25.71 11 26.35 7 26.75 13 27.24 16 27.66 9 27.95 6 28.40 5 28.68 9 29.87 6 30.76 8 31.37 4 31.67 4 31.99 6 32.53 4 32, 80 5 33.55 7 35.20 5 36.93 5 37.58 5 44.54 6 45.70 4

The table above shows the positions of the highs (in 2 Theta), as JJÒ, 11/57

also the relative intensities of the maximums of the diagram. The most intense maximum value was normalized here at a relative intensity of 100.

Another object of the invention is a crystalline form A of the compound 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate of formula (I) (Polymorph A), characterized by a diagram of X-rays corresponding to one or more of the following reflexes: 9.38 (100), 9.94 (5) and 10.35 (8) (each ± 0.5 in 2 jheta, the relative intensity is indicated between parenthesis). The powder X-ray diffraction diagram may additionally have one or more of the following reflections: 12.76 (6), 15.94 (43), 17.54 (15), 19.28 (8), 28 , 68 (9) and 31.99 (6) (each ±

0.2 in 2 Theta) relative intensity in parentheses.

Another object of the invention is a crystalline form A of the 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate compound of formula (I) which has a characteristic Raman spectrum with characteristic lines. , expressed in

wave numbers (cm'1).

Position (cm "') Intensity 3060 M 3040 M 3021 M 2986 M 2966 S 2933 S 2920 S 2895 M 2879 M 2856 S 3O 12/57

2892 W 1690 M 1616 M 1601 M 1569 Vw 1467 M 1443 M

Position (cm "') Intensity 1412 W 1389 M 1361 W 1351 M 1332 W 1322 W 1306 W 1295 W 1289 W 1273 M 1247 M 1227 W 1211 M 1177 W 1167 W 31 1W

1122 Vw 1106 W 1081 W 1076 W 1055 M 1047 M 1025 W 999 Vs 971 V 957 M 929 W 901 W 855 M 843 M 817 W 796 W 754 M 707 Vw 676 6w 635 M 614 W 572 Vw 536 M 514 Vw 486

Vw

Position (cm "') Intensity 468 Vw 454 W 425 Vw 400 W 359 W 345 W 328 M 292 M 272 M 247 S 188 W 118 Vs 105 Vs 81 Vs

(dimethylamino) methyl- (cyclohex-1-yl)] -phenol maleate of Formula (I) 1 comprising one or more of the following characteristic bands in the Raman spectrum, each expressed in wavelength numbers (cm-1): 118 (vs), 188 (w), 400 (w), 676 (w), 2812 (w), 2879 (m), preferably one or more of the following bands: 118 (v), 188 (w), 292 ( m), 328 (m), 359 (w), 400 (w), 486 (vw), 676 (w), 901 (w), 1025 (w), 1273 (m), 1351 (m), 1412 ( w), 1569 (vw), 1601 (m), 1690 (m), 2812 (w), 2879 (m), 2986 (m),

3060 (m). Another object of the invention is also a Crystalline Form A of the compound 3- [2- (dimethylamino) methyl- (cyclohex-1-yl] -phenol maleate of formula (I), which presents an X-ray diffraction diagram as follows: as observed in Figure 1.

Another object of the invention is also a Crystalline Form A of the compound 3- [2 (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate of formula (I), which presents

a Raman spectrum as seen in Figure 2.

Crystalline form A is a low temperature stable thermodynamic form of up to, for example, approximately 100 ° C and additionally exhibits excellent chemical and physical stability. Polymorph A is even sensitive and stable to the influence of humidity in the presence of high relative humidity of up to 90%, even over extended periods of time. No water absorption, no hydrate formation and no conversion to other forms that crystallized under normal conditions were observed. Polymorph A also has no phase transformations in contact with air and in the presence of moisture. Polymorph A also does not change under high pressure or during grinding and does not convert to other crystalline forms under high pressure. Polymorph A is also non-hygroscopic and only absorbs small amounts of surface moisture. Under these conditions Polymorph A also does not form solvents and in contact with solvents no conversion is observed. The solution in polar solvents is very good. The melting point is approximately 167 ° C and the enthalpy of melting is approximately 135 J / g. Polymorph A can be made as a solid powder with an average particle size, which is generally in the range of 1pm to approximately 500 pm. Crystalline Form A, based on these properties, is particularly suitable for the manufacture of pharmaceutical compositions. The compound of formula (I) forms at higher temperatures, thermodynamically stable crystalline Form B, which under normal conditions is also stable in contact with air and atmospheric humidity. The crystalline form is also so manipulable that it can be employed in the manufacture of pharmaceutical compositions. Another object of the invention is a crystalline form of the 3- [2 (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate compound of formula (I), which presents a characteristic X-ray dysfunctional diagram in the order from 2nd to 35 ° 2 Thetal with "d" values (Angstrom):

10.6 (m), 7.5 (m), 7.3 (m), 6.1 (s), 5.29 (s) 4.88 (m), 4.72 (m), 4, 47 (vs), 4.43 (m), 4.26 (m), 4.24 (m), 3.99 (s), 3.71 (m), 3.52 (m), 3.30 (s); called the

continued as Form B.

Another object of the invention is a crystalline form B of the 3- [2 (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate compound of formula (I), which presents a characteristic X-ray dysfunctional diagram, with the following specially marked reflections.

2 Theta Relative intensity 8.36 18 11.85 20 12.19 20 13.41 12 14.50 49 14.83 11 16.77 58 18.16 17

ν- '

18.78 28 19.84 100 20.00 17 20.84 19 20.97 16 21.19 12 22.27 33 22.64 7 22.85 11 23.95 18 24.53 7 24.85 8 25, 26 16 25.97 8 26.66 12 27.00 29 27.18 13 27.48 8 28.21 4 29.10 6 29.41 9

The previous table shows the positions of the highs (in 2 Theta), as well as the relative intensities of the highs. The most intense maximum normalizes here according to a relative intensity of 100.

Another object of the invention is a polymorph B of the compound 3- [2- (dimethylamino-methyl- (cyclohex-1-yl)] -phenyl maleate of formula (I), characterized by a powder X-ray diffraction diagram, which comprises one or more of the following reflections: 8.36 (18), 14.5 (49) and 14.83 (11) (each within ± 0.5 in 2 Theta, the relative intensity is indicated in parenthesis). Preferably1 the powdered diffraction diagram may additionally present one or more of the following reflections 11,85 (20), 12,19 (20), 18,16 (17), 22,85 (11), 29,1 (6) and 29.41 (6) (each ± 0.2 in 2 Theta, relative intensity indicated in parenthesis).

Another object of the invention is a crystalline Form B of the compound 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate of formula (I) which has a characteristic Raman spectrum having the following lines, expressed as wave numbers (cm1):

Position (cm "') Intensity 3045 Vs 3028 M 2974 S 2953 S 2928 Vs 2896 S 2856 S 2829 M

1703 S 1621 M 1612 M 1583 M 2> Ύ

1480 V 1459 M 1446 M 1401 V 1385 M 1360 S 1227 V 1324 W 1313 M 1309 M 1295 M 1282 M 1253 W 1220 W 1211 M 1197 M 1178 W 1162 M 1124 W 1004 W 1076 W 1052 M 1010 W

999 Vs 971 Vw 956 W 933 W Position (cm -1) Intensity 890 W 875 M 858 M 841 S 816 M 794 M 750 M 708 Vw 628 W 620 W 605 Vw 578 W 573 W 538 M 507 Vw 472 W 455 W 449 W 21/57

418 W 372 W 340 M 307 W 272 M 246 S 229 M 101 Vs 83 Vs

[2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate of formula (I), which comprises one or more of the following characteristic bands in the Raman1 spectrum each expressed as a wavelength (cm ' 1): 229 (m), 875 (m) and 2829 (m), preferably one or more of the following bands: 229 (m), 307 (w), 372 (w), 605 (vw). 875 (m), 890 (w), 1010 (w) 1197 (m), 1401 (vw), 1480 (vw), 1583 (m),

1703 (s), 2829 (m), 2953 (s).

Another object of the invention is a Crystalline Form B of the compound 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate of formula (I), which presents an X-ray diffraction diagram as that of Figure 3.

Another object of the invention is a crystalline form B of the compound 3- [2 (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate of formula (I) which has a Raman spectrum as seen in Figure 4

Polymorph Form B can be converted to Crystalline Form A. Forms A and B form an enanti-tropic system with a transition point or transition order of approximately 100 to 120 ° C. So too are a goal of MO 22/57

invention of the mixtures of Crystalline Forms AeB according to any proportion of the mixture. Crystalline Form B is the most stable thermodynamic form at elevated temperatures, such as, for example, at least 100 ° C or higher. Polymorph B also has excellent chemical stability at elevated temperatures, also in the presence of air humidity. Physical stability is reduced due to the higher pressure and also at higher temperatures, with or without the influence of moisture, converting to Polymorph A. However, neither water absorption nor hydrate formation is observed. . Polymorph B does not form solvates either. Conversion with solvents can be converted to Crystalline Form A. Solubility in polar solvents is very good and comparable to Solubility of Polymorph A. Melting point is approximately 178 ° C and melting enthalpy of approximately 125 J / gram. Polymorph B can be manufactured as a solid powder material with medium particle sizes, which are generally in the order of 1 µm to approximately 500 µm. Storage of crystalline Form B under dry protective gas (nitrogen) is recommended.

Polymorphic forms may be prepared according to known crystallization procedures from 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate salt, for example by stirring suspensions (establishing phase equilibria), precipitation, recrystallization or evaporation of solvent agents. Saturated or supersaturated solutions may be employed, with or without inoculation of crystallizing core forming agents. Solution formation temperatures can reach 100 ° C. Crystallization may be initiated by cooling from approximately -100 to 30 ° C, preferably from -30 ° C to 20 ° C, and the cooling may be carried out in a continuous or stepwise mode. In preparing the solutions or suspensions, amorphous or crystalline starting materials may be employed to obtain high concentrations in the solutions and to obtain other crystalline forms.

Another object of the invention is also a procedure for manufacturing Crystalline Form A of 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate compound, characterized in that it is:

(a) a solid, powdery, amorphous form of 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate with an inert gas containing water vapor, or

(b) An amorphous form suspension of 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate is prepared in a solvent as a carrier and stirred until complete formation of the Form. crystal A, or

(c) 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate are dissolved in a solvent and then precipitated; or

(d) 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate, phenol and maleic acid are combined, where preferably at least one of these components is present in a dissolved or suspended form. The product obtained is then isolated, provided that the temperature does not exceed 100 ° C.

In steps (a) and (b) of the procedure, the temperature rises to a maximum of 40 ° C and the preparation procedure is preferably carried out at room temperature. Inert gases are, for example, air, nitrogen and noble gases, where air is preferred, given economic reasons. The relative humidity of the gases may be, for example, from 40 to 90% and preferably 60 to 90%. The treatment time in the procedure (a) depends mainly on the particle size and relative humidity, for example from 5 to 100 hours.

In step (a) of the procedure Polymorph B may also be formed in addition to Form A if the relative humidity is too low and / or the treatment time is too short: After the isolation phase, the crystalline residue in the usual manner, conveniently avoiding temperatures above 100 ° C.

Step (b) preferably develops from -20 ° C to 40 ° C, and particularly preferably (-) 5 ° C to 25 ° C (approximately at room temperature).

Suitable solvents have been mentioned above. The treatment time in step (b) of the procedure can be from 5 to 100 hours. After isolation of the product, the solvent used or the solvent mixture can be removed in the usual manner by known drying procedures.

In step (c) of the procedure crystalline Form A, B or the amorphous Form of 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate may be used to prepare solutions.

The concentration of 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate in the solution depends on the temperature chosen and the solvent. The dissolved amount may amount to, for example, 0.5 to 50, preferably 0.5 to 30, particularly preferably 0.5 to 20 and especially preferably 1 to 15 weight percent, based on the solvent: the dissolution temperature may be up to 100 ° C and preferably up to 60 ° C. The solution may also be prepared at room temperature, solvents having a high dissolution capacity such as water, dimethyl formamide, dimethyl sulfoxide, methanol, ethanol, N-methyl pyrrolidone and propylene glycol are applied.

Precipitation may be effected by cooling or cooling, Mb 25/57

partial or total elimination of the solvent, incorporation of a precipitating agent (a non-solvent agent, for example heptane or methyl t-butyl ether) or by a combination of these measures. Cooling can mean slow cooling or rapid cooling to temperatures up to -20 ° C and preferably up to 0 ° C. The dissolving agent may be an increase in the gas stream, vacuum application or by a combination of these measures.

The term heating to remove the solvent means in step (c) of the procedure the application of a temperature of up to 70 ° C and preferably up to 50 ° C. Precipitate procedures according to step (c) of the procedure are preferably used in the manufacture of polymorph Form A.

In step (d) the processing temperature preferably does not exceed 90 ° C, preferably not more than 70 ° C and particularly preferably not more than 60 ° C. Generally, the dissolution temperature of a component is higher than

mixing temperature.

Another object of the invention is a salt of maleic acid formula (I) and 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol in crystalline Form A (Polymorph A) which may be obtain by one of the procedures described above.

While the preparation of polymorph Form A is relatively non-critical, polymorph Form B can only be obtained by a special procedure. Surprisingly it has been found that Form B can be obtained in a reproducible form by an evaporative process in specific solvent combination and high evaporation temperatures.

Thus, another object of the invention is a procedure for preparing crystalline Form B of 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate compound, Mm 26/57 V2.

characterized in that 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate is dissolved in a mixture formed by tetrahydrofuran and water at a volumetric ratio of 0.8: 1, 2 to 1.2: 0.8, and then the solvent mixture is completely eliminated at a temperature of at least 80 ° C. Lower evaporation temperatures are also possible, operating in an open atmosphere, for example at room temperature in an open container (contact with atmospheric humidity).

Tetrahydrofuran (THF) and water preferably have a volumetric ratio of 1: 1. Prior to disposal of the solvent mixture the solution may be stirred for a specified period of time, for example up to 24 hours at elevated temperature (approximately 80 to 100 ° C).

To remove the solvent mixture a gaseous and / or vacuum stream may additionally be applied. Heating to remove the solvent means a temperature of at least 80 ° C and preferably up to 120 ° C and especially

preferably 90 to 100 ° C.

The solvent is preferably removed by distillation on the rotary evaporator. The amount of 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate in the mixture of THF and water may preferably be 0.5 to 20, preferably 0.5 to 10%. percent by weight, referring to the mixture of THF and water. It was also found that the adjustment of phase equilibria by means of

stirring the suspensions at temperatures of at least 120 ° C leads to the formation of crystalline Form B.

Another object of the present invention is a salt of formula (I) of maleic acid and 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol in crystalline Form B (Polymorph B) which may be obtained. by one of the written procedures 27/57

previously.

3- [2- (Dimethylamino) methyl- (cyclohex-1-yl)] -phenol maleate, based on an advantageous global properties profile, is very suitable for use as an active ingredient in pharmaceutical compositions, and especially for pharmaceuticals. intended to soothe pain or painkillers. Therefore, it is also an object of the invention to use the compound 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate of formula (I) as an active ingredient in analgesic drugs. Also considered herein are, as in all circumstances, diastereoisomers or mixtures of diastereoisomeric enantiomers which have a phenyl ring and dimethylaminomethyl group configuration (1R, 2R or 1S, 2S configuration), where particularly enantiomer with the absolute configuration (1R, 2R).

Another object of the invention is a pharmaceutical composition containing an effective amount of the compound 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate of formula (I) and a pharmaceutically acceptable carrier or agent. filling or pharmaceutical dilution.

In said composition the compound of formula (I) may be present as Crystalline Form A, Crystalline Form B or as a mixture of Forms AeB. Preferably, the composition contains Crystalline Form A. The amount of the compounds of formula (1) basically depends on the type of

formulation and the desired dosage during the administration period. The amount to be administered to patients of each of the salts of the invention may vary depending, for example, on the patient's body weight or age, as well as the type of application, the indication to be treated and the severity of the disease. Usually 0.005 to 5000 mg / kg, preferably 0.05 to 500 mg / kg body weight of the patient of at least one such compound is applied.

In the case of oral formulations they may be solid formulations, for example tablets, capsules, tablets and lozenges. In oral formulations may be liquid formulations, for example solutions, suspensions, syrups or elixirs. Liquid and solid formulations also comprise incorporation of the compounds of formula (I) into solid or liquid foods. Furthermore, they comprise liquids and solutions suitable for parenteral application, such as for example an infusion or injection.

The compounds of formula (I) and the crystalline forms may be used directly as powders (micronized particles), granulates, suspensions or solutions, or they may be mixed with other ingredients and compounds suitable for spraying, to charge the powders. in hard or soft gelatin capsules, compress into tablets, tablets or lozenges, or suspend powders in a vehicle or dissolve to prepare suspensions, syrups or elixirs.

Tablets, tablets or tablets may then be provided with a coating or coating.

Pharmaceutically acceptable additives for different types of formulations are known in the art. These may be, for example, binding agents such as synthetic or natural polymers, drug carriers, sliding agents, surfactants, sweeteners and aromatic substances, coating substances, preserving agents, colorants, thickening agents, auxiliary agents, antimicrobial substances and vehicles or supports for different types of formulations. Examples of binding agents are arabic rubber, rubber My 29/57 ^

tragacanth, acacia rubber and biodegradable polymers such as dicarboxylic acid homo- and copolyesters, alkyl etherols, polyalkylglycols and / or aliphatic hydroxycarboxylic acids and dicarboxylic acid homo- and copolyamides, alkyl diamines and / or acids aliphatic aminocarboxylic acids; polyester-polyamide copolymer compounds, polyanhydrides, polyesters,

polyphosphates and polycarbonates.

Biologically degradable polymers may be of linear, branched or crosslinked type. Specific examples are polyglycolic acid, polylactic acid and poly-1,1-lactic / glycolic acid. Other examples of the polymers are water soluble polymers, such as, for example, polyoxyalkylenes (polyoxyethylene, polyoxypropylene and the mixture polymers thereof), polyacrylamides and alkylated hydroxy polyacrylamides, polymaleic acid and esters or amides thereof. polyacrylic acid and esters or amides thereof, polyvinyl alcohol and esters or ethers thereof, polyvinylimidazole, polyvinylpyrrolidone and natural polymers such as for example chitosan.

Examples of vehicles or carriers are phosphates such as phosphate

dicalcium.

Examples of slip or flow agents are natural or synthetic oils, greases, waxes or fatty acid salts such as magnesium stearate.

Surfactants (surfactants) may be anionic, cationic, amphoteric or neutral in nature. Examples of surfactants are lecithin, phospholipids, octyl sulfate, decyl sulfate, dodecyl sulfate, tetradecyl sulfate, hexadecyl sulfate and octadecyl sulfate, sodium oleate or sodium caprate, 1-acyl aminoethane-2-sulfonic acids , such as 1-octanoylamino ethane-2-sulfonic acid, 1-decanoylamino-ethane-2-sulfonic acid, 1-dodecanoylamino-ethane-2-sulfonic acid, 1-tetradecanoylamino-ethane-2 -sulfonic acid, 1-hexanoyl-amino ethane-2-sulfonic acid and 1-octadecanoyl-amino ethane-2-sulfonic acid, bile acids, salts and derivatives thereof, such as, for example, cholic acid, deoxy cholic acid, tauro cholic acid, tauro deoxy cholic acid and sodium glycocholate, sodium caprate, sodium laurate, sodium oleate, sodium lauryl sulfate, sodium cetyl sulfate, dihydrate sulfosuccinate sodium, cocamidopropyl and lauryl betaine, fatty alcohols, cholesters gols, glycerine mono- distearate, glycerine mono- dioleate, glycerine mono- dipalmitate and polyoxyethylene stearate.

Examples of sweetening agents are sucrose, fructose, lactose or aspartame.

Examples of aromatic substances are peppermint, vinca oil or fruit aromas such as cherry or orange flavoring.

Examples of coating substances are gelatin, waxes, varnishes,

sugar or biological degradation polymers.

Examples of preserving agents are methyl or propyl paraben, acid

sorbic, chlorobutanol and phenol.

Examples of auxiliary substances are perfumes.

Examples of the thickening agents are synthetic polymers, fatty acids, fatty acid salts, fatty acid esters and fatty alcohols.

Examples of liquid carriers are water, alcohols (ethanol, glycerine or propanethriol, propylene glycol, liquid polyethylene glycols, polytriazines and olive oils).

Examples of solid carriers or carriers are talc, arches, microcrystalline cellulose, silicon dioxide, aluminum oxide and the like solids.

The composition or formulation according to the invention may also contain isotonic agents, such as for example sugar, physiological pH regulating agents and sodium chloride.

The composition according to the invention may also be formulated as an effervescent tablet or an effervescent powder which decomposes in an aqueous environment with preparation of suspension solutions for drinking.

A syrup or elixir may contain the compound of formula (I), a sugar such as sucrose or fruit as sweetening agents, a preserving agent (such as methylparaben), a colorant and a flavoring agent (such as aromatic substances).

The composition according to the invention may also be a formulation with

a delayed and controlled release of the active ingredient in contact with body fluids from the gastrointestinal tract, in order to achieve a substantially constant and effective level of the active ingredient in blood plasma.

The compounds of formula (I) may for this purpose be incorporated into a polymer matrix of a biological degradable polymer, a water soluble polymer of both polymers, optionally together with a suitable surfactant. Incorporation may mean in this context the incorporation of microparticles into the polymeric matrix. Those formulations which have a delayed or controlled release of the active ingredient may also be obtained by encapsulating dispersed microparticles or emulsified microglets through known dispersion and emulsion coating technologies.

The compounds of formula (I) may be employed in conjunction with at least one additional active ingredient intended for combination therapies. For such purpose at least one active ingredient may be dispersed or dissolved in the composition according to the invention. 32/57

Another object of the invention is the use of the 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate compound of formula (I) in the manufacture of a pharmaceutical composition or formulation preferably for the treatment of conditions of pain.

Another object of the invention is a procedure for the treatment of

pain situations, whereby a patient in pain is administered an effective amount of the compound 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] -phenol maleate of formula (I).

The medicament according to the present invention (the pharmaceutical composition or formulation according to the invention) is especially suitable for pain prophylaxis and / or treatment, preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain and pain. visceral pain; migraine; depression. Neurodegenerative diseases, preferably selected from the group formed by the Morbus Parkinson1 morbus Alzheimer, Huntington morbus, multiple sclerosis; the diseases of knowledge, preferably the lack of knowledge, especially the attentional deficit syndrome (ADS), the panic stages; epilepsy; cough; bladder or urine incontinence; diarrhea; pruritus; schizophrenia; cerebral ischemia; muscle spasms; cramps; changes in diet, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; misuse of alcohol and / or drugs (especially nicotine and / or cocaine dependence) and misuse of drugs, alcohol and / or drug dependence (especially nicotine and / or cocaine) and medicines; preferably for prophylaxis and / or reduction of manifestations derived from the suspension of alcohol and / or drug dependence (especially nicotine and / or cocaine) and / or drug dependence; 33/57 V ^

development of manifestations of tolerance towards drugs, especially opioids; of esophageal stomach reflux syndrome; for diuresis, for antinatriuresis; to influence the cardiovascular system, for anxiolisis; to increase the state of surveillance; to increase libido; to modulate movement activity and for local anesthesia.

The medicament (the pharmaceutical composition of the invention) of the present invention is especially suitable for prophylaxis and / or treatment of pain, preferably acute pain, chronic pain, neuropathic pain or visceral pain; of depression; epilepsy; Parkinson's morbus, alcohol and / or drug misuse (preferably nicotine and / or cocaine) and / or drug misuse, alcohol and / or drug dependence (preferably nicotine and / or cocaine) and / or drug dependence; preferably for prophylaxis and / or reduction of manifestations derived from the unaccustomed dependence on alcohol and / or drugs (preferably nicotine and / or cocaine) 15 and / or drug dependence; the development of manifestations of tolerance towards drugs, especially against opioid drugs;

or for anxiolisis (as anxiolytics).

Particularly advantageous is the use of at least one salt according to the invention, each optionally in the form of one of its pure stereoisomers, preferably enantiomers or diastereoisomers, their racemates or in the form of a mixture of stereoisomers, preferably enantiomers and / or diastereoisomers, in any mixing ratio, as well as one or more pharmaceutically tolerable auxiliary substances in the manufacture of a medicament for prophylaxis and / or pain management, preferably selected from the group consisting of acute pain, chronic pain, pain 34 Neuropathic pain, and visceral pain of migraine, depressions, neurodegenerative diseases, preferably selected from the group formed by the Parkinson's morbus Morbus Alzheimer's, Huntington's morbus and multiple sclerosis; diseases of knowledge, preferably states of lack of knowledge, particularly attentional deficit syndrome (ADS), panic attacks; epilepsy; cough; urinary incontinence; diarrhea; pruritus; schizophrenia; cerebral ischemia; the muscle spasms; cramps; eating disorders or disorders, preferably selected from bulimia, cachexia, anorexia and obesity, misuse of alcohol and / or drugs (preferably misuse of nicotine and / or cocaine) and misuse of medicines; alcohol and / or drug dependence (preferably nicotine and / or cocaine) and / or drug dependence, preferably for prophylaxis and / or reduction of manifestations derived from the suspension of alcohol dependence and / or drugs (especially nicotine and / or cocaine) and / or drug dependence; the development of manifestations of tolerance to drugs and / or medications, preferably opioids, of stomach-esophageal reflux syndrome; for diuresis, for antinatriuresis; to influence the cardiovascular system, for anxiolisis; to increase vigilance; to increase libido; for modulation of movement activity and for local anesthesia. The medicament of the invention may be in the form of a pharmaceutical form.

liquid, semi-solid or solid, for example, in the form of injectable solutions, drops, juices, syrups, powders, suspensions, tablets, capsules, veins, suppositories, aerosols, or in multiparticulate form, for example, in pellet form, globules or granules, optionally formed as tablets, capsule-filled or suspended in a liquid, to be administered as such. Moreover, of at least one salt according to the invention, optionally in the form of pure stereoisomers thereof, preferably enantiomers or diastereomers thereof, racemate in the form of mixtures of stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, in The medicament of the invention (the pharmaceutical composition of the invention) contains the pharmaceutically acceptable auxiliary substances, preferably chosen from the group consisting of support or carrier materials, filler materials, solvents, diluents, surfactants, colorants, preservatives, disintegrants, sliding agents, lubricants, aromatic substances and binders.

The choice of physiologically acceptable auxiliary substances, as well as the amounts to be applied to them, depends on the route of administration of the drug (the pharmaceutical composition), whether oral, subcutaneous, parenteral, intraveious, intradermal, intramuscular, intranasal, buccal , rectal or topical, for example on infections of the skin, mucous membranes and eyes. Preferably for oral application are formulations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups; For parenteral, topical and inhalant application, solutions, suspensions, easy-to-reconstitute dry preparations and sprays are preferably suitable.

Suitable percutaneous preparations are also delayed release preparations in dilute form | or well with the addition of media required for skin penetration.

Usable forms of oral or percutaneous preparation may differently release the respective salts according to the invention. The preparation of medicaments according to the invention is usually carried out by methods, devices and means already known in the state of the art and procedures, such as those described by way of example in "Remington1S Pharmaceutical Sciences", AR Gennaro1 editor, 17th edition, Mack Publishing Company, Easton, Pa1 1985, especially vol. 8, chapters 76 to 93. The corresponding description will be taken as a reference herein and if

consider as part of the disclosure.

The amount of the corresponding salts according to the invention to be administered to patients may vary and thus depends on the patient's weight or age, as well as on the type of application, indications and severity of the disease. Usually at least between 0.005 and 5,000 mg / kg, preferably between 0.05 and 500 mg / kg of the patient's body weight of a

particular composition.

The following examples illustrate in more detail the invention without limiting

to them. Examples

In all differential scanned poe calorimetry (DSC) measurements - except where otherwise stated - heating rates rise to 10 ° C / min, as long as the indicated temperatures are

maximums.

A) Elaboration of (+ W1R.2RV3-2- (dimethylamino) methyl- (cyclohex-1-

iiyi-phenol maleate Example A1: Preparation as Crystalline Form A

0.0685 g of (+) - (1R, 2R) -3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol are diluted in 0.4 mL of ethyl acetate. Additionally a second solution of 0.0371 g of maleic acid in 1 ml of ethyl acetate is added. Both solutions are combined at room temperature and mixed by stirring, from which an off-white precipitate forms. The mixture is heated by stirring to 50 ° C and then cooled back to room temperature. Afterwards the precipitate is filtered through a glass frit, washed with 4 ml of ethyl acetate and the residue is dried while air is aspirated for 5 minutes. A content of 0.0870 mg (85% of the theory) of (+) - (1R, 2R) -3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate is shown. as an off-white crystalline dry extract with a melting point of approximately 167 ° C and the enthalpy of melting amounts to approximately 135 J / g determined by DSC at a heating rate of 10 ° C / min. The crystalline dry extract is the polymorphic Form A1 whose X-ray diffraction is illustrated in Figure 1. The Raman spectrum

illustrated in Figure 2.

When occupying a double amount in (+) - (1 R, 2R) -3- [2-

(dimethylamino) methyl- (cyclohex-1-yl)] -phenol, only 1: 1 maleate is formed. Example A2: Elaboration as Crystalline Form A

6.22 g (53.5 mmol) of maleic acid in 130 ml of acetic acid ethyl ester are diluted in a glass flask and then added by dripping with stirring to a tempered solution at 50 ° C of 12 ° C. 48 g (53.5 mmol) of (+) - (1R, 2R) -3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol in 40 ml of acetic acid ethyl ester. After the addition of 20 to 25 ml, an off-white precipitate forms. After addition of the total solution, the off-white crystalline dry extract is filtered from the hot solution and washed with rather cold acetic acid ethyl ester. The residue is dried by continuous air aspiration. A content of 18.38 g (98.3% of theory) of (+) - (1R, 2R) -3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] -phenol is present. 38/57 V- 'maleate as Crystalline Form A (according to the X-ray diffraction diagram) with a reference point of 177-179 ° C. Two maximum ridges were found at 165.5 and 177.2 ° C by DSC analysis.

g of the dry extract is dried in a drying chamber at 40 ° C and between 80 and 90 mbar from night to morning. The weight loss only amounts to 3.8 mg (ethyl acetate). X-ray diffraction corresponds to Form A; the maximum DSC remains almost unchanged, 165.8 and 176.7. Example A3: Elaboration as Crystalline Form B

1.95 g of (+) - (1 R, 2R) -3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] -phenol are diluted at room temperature in 40 ml of acetic acid ethyl ester. Then a solution of 0.97 g of maleic acid to 25 ml of acetic acid ethyl ester is added dropwise at room temperature. After adding to approximately half of the solution a turbidity forms and then a crystalline precipitate. The suspension is stirred at 70 ° C for one hour in a rotary evaporator and then cooled to room temperature. Then the suspension is cooled in a refrigerator and the precipitate is filtered off. The fixed residue is washed once with 4 ml of acetic acid ethyl ester and dried by continuous air aspiration (5 minutes). A content of 2.815 g (96.4% of Theory) of (+) - (1R, 2R) -3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate appears as Form crystal B (according to the X-ray diffraction diagram) with a reference point of 177-179 ° C. A maximum of ΜΙ, ΤΟ was found by DSC analysis.

Example A4: Elaboration as Crystalline Form A

In a glass flask at 55 ° C 8.92 g of acetic acid is diluted in 120 ml of acetic acid ethyl ester. In another glass of glass at 55 ° C, 17.96 is diluted 39/57 V ^

(+) - (1R, 2R) -3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol at room temperature in 108 ml of acetic acid ethyl ester and drop by drip slowly to the maleic acid solution within 30 minutes. After the addition of approximately half, a whitish, voluminously crystalline dry extract is formed. Upon complete addition, the suspension is stirred for 3 hours at 55 ° C. Then allow to cool to room temperature and continue stirring overnight. The residue is filtered by washing it with 20 ml of acetic acid ethyl ester and drying by continuous air aspiration (5 minutes). A content of 26.26 g (97.7% of theory) of (+) - (1R, 2R) -3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate appears. as Crystalline Form A (according to the X-ray diffraction diagram). Two maximums of 166.03 and 177.03 ° C were found by DSC analysis. Example A5: Elaboration as Crystalline Form A

2.33 g of (+) - (1R, 2R) -3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol at room temperature are diluted in 15 ml of ethyl ester in a glass flask. of acetic acid, or 1.16 g of maleic acid in 30 ml of acetic acid ethyl ester. In another glass flask, 20 ml of acetic acid ethyl ester are heated to 45 ° C and then under stirring, both solutions are dripped simultaneously. A strong turbidity forms spontaneously. After the addition is complete, the suspension is stirred for a further 3 hours at 50 ° C. Afterwards it is allowed to cool itself at room temperature. The residue is filtered by washing it with 10 ml of acetic acid ethyl ester and drying by continuous air aspiration (5 minutes). 3.41 g (97.7% of theory) content of (+) - (1R, 2R) - 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate as Crystalline form A (according to X-ray diffraction diagram). Two maxima of 166.03 and 177.03 ° C were found by DSC analysis.

Example A6: Preparation of (+) - (1R, 2R) -3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate

a) Preparation

In a 1 liter three neck pool, 24.64 g of (+) - (1R, 2R) -3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] -phenol (76.8% purity after HPLC analysis) in 500 ml of acetic acid ethyl ester. Warm to 55 ° C and add with stirring to 9.44 g of maleic acid at one time. Stir at said temperature for 4 hours and then for 2 hours at 20 ° C. The residue is then filtered, washed with 20 ml of acetic acid ethyl ester and then dried by continuous aspiration of air. In the thermoanalysis (DSC) endothermic signals were found at 150.4 ° C and 157.7 ° C. Purity (relative to phenol) is 84.4% by HPLC analysis. The yield amounts to 27,57 g (97,0% of the theory).

b) Purification by washing with stirring.

The thus obtained crude product is stirred in a glass flask, transferred with the solvent to a thermal mixer at 50 ° C and mixed for 4 hours. Then the solutions cool overnight at 23 ° C and filter. The yield and purity (HPLC) of the residue is determined. Further indications are given in the following Table 1. The following abbreviations are used: EtAc is ethyl acetate; EtOH to ethanol; PrOH is i-propanol; AcNi to acetonitrile; All is toluene; Hex to n-hexane; DiEt is diethylether; BuMe is t-butyl methylether; Ace acetone; MeEt is methyl ethyl acetone, THF is tetrahydrofuran.

Table 1:

Quantity Solvent 1 Solvent 2 Yield Purity 53

maleate (mg) (ml) (ml) (%) (%) 56.3 EtAc (1.0) - 97.2 84.6 55.9 PrOH (1.0) - 73.0 96.7 56 Hex (1.0) - 96.3 84.0 55.8 AcNi (1.0) - 71.5 93.6 56.4 Tol (1.0) - 97.2 84.0 62.6 DiEt (1.0) - 97.0 84.6 53.5 BuMe (1.0) - 97.4 84.2 55.2 Ace (1.0) - 58.2 97.9 55.1 MeEt ( 1.0) - 75.9 92.1 58.8 THF (1.0) - 80.1 89.5 55.2 Aee (0.98) EtOH (0.02) 52.0 97.9 60, 4 Aee (0.96) EtOH (0.04) 50.5 97.0 55.5 Aee (0.94) EtOH (0.06) 37.1 98.2 58.2 Aee (0.92) EtOH (0.08) 42.4 98.3 57.3 Ace (0.90) EtOH (0.10) 39.6 98.2 517.1 PrOH (10.0) - 79.7 88.9 516, 5 PrOH (10.0) - 79.4 87.5 511.2 PrOH (10.0) - 80.7 89.0 516.4 Ace (10.0) - 62.0 98.1 515.2 Aee (10O) - 64.8 96.4 511.6 Aee (10.0) - 68.7 94.8 506.9 THF (10.0) - 82.9 87.9

ΤΠΤ

507.2

518.3 514 ^ "509.8

THF (10.0) THF (10.0) Ace (9.70) Ace (9.70) Ace (9.70)

EtOH (0.3) EtOH (0.3) EtOH (0.3)

81.9

83.8

48.3

5Õ1T

5Õ2

87.8

"88Τ

~ 98 ^ Γ 98.7

-The product can be obtained from good to excellent purification by

cleaning the crude product by washing with stirring.

(+ V (1R, 9RV3-r2- (dimethyl) minn) methyl- (cyclohex-1-

ii)] - amorphous fpnnl-maleate

Example B1: Lyophilization

81.5 mg of maleate prepared according to Example are diluted.

A1 in 3 ml of water and cool to -75 ° C. Then lyophilize at room temperature.

mentioned and under a pressure of 0,011 mbar for 23 hours. A

quantitative content of off-white solid residue which in the presence of

humidity tends to rapid crystallization, essentially under the formation of

Crystalline Form A. By Differential Scanning Calorimetry (DSC,

10 ° C / min) a transition temperature is determined

vitreous at 30 ° C. An exothermic maximum of 85 ° C is due to a

crystallization. The crystalline material formed melts at 178 ° C.

Storing 20 mg of Amorphous Form at room temperature with 20% or 90% atmospheric humidity for 24 hours gives a mixture of crystalline forms A and B, as well as crystalline form AC) Preparation of crystalline form AA crystalline form is determined by the difference in spectrum

Raman, unless otherwise indicated. 43/57 v ^ ^ Example C1: Non-Solvent Precipitation

a) Precipitation with n-heptane

80 mg of the maleate prepared according to Example A1 is diluted at room temperature in 8 ml of acetone. After stirring with 7.5 ml of n-heptane. An off-white precipitate forms, which is filtered and dried in an air stream at room temperature. A 50 mg content of off-white powder appears, which corresponds to crystalline Form A.

b) Precipitation with n-heptane

80 mg of the maleate prepared according to Example A1 is diluted at room temperature in 17 ml of tetrahydrofuran (THF). Then stir with 9 ml of n-heptane. An off-white precipitate forms, which is filtered and dried in an air stream at room temperature. A 52 mg content of off-white powder appears, which corresponds to crystalline Form A.

(c) Precipitation with tertiary methyl butyl ether (MTBE) by

your acronyms in English)

80 mg of the maleate prepared according to Example A1 is diluted with

room temperature in 21 ml THF. Ensured by stirring with 7.5 ml MTBE. An off-white precipitate forms, which is filtered and dried in an air stream at room temperature. A content of 48 mg of off-white powder corresponding to crystalline Form A appears. Example C2: Phase equilibrium with suspensions a) Suspension in acetone To 80 mg of the maleate prepared according to Example B1 is added 0.5 ml of acetone and Stir for 24 hours at room temperature. It is then filtered and dried in an air stream at room temperature. A 52 mg content of 52 mg of crystalline Form A appears as off-white powder.

b) Suspension in 1,4-dioxane

At 80 mg of the maleate according to Example B1, 0.5 ml of 1,4-dioxane is added and stirred for 24 hours at room temperature. It is then filtered and dried in an air stream at room temperature. A 47 mg content of Crystalline Form A appears as off-white powder.

c) Suspension in ethyl acetate

To 80 mg of the maleate prepared according to Example B1 is added 0.5 ml of ethyl acetate and stirred for 24 hours at room temperature. It is then filtered and dried in an air stream at room temperature. A 50 mg content of Crystalline Form A appears as off-white powder.

d) Suspension in water

To 80 mg of the maleate prepared according to Example B1 is added 0.1 ml and then again 0.2 ml of water and stirred for 24 hours at room temperature. It is then filtered and dried in an air stream at room temperature. A 49 mg content of Crystalline Form A appears as off-white powder.

e) Isopropanol suspension

To 80 mg of the maleate prepared according to Example B1 is added 0.5 ml of isopropanol and stirred for 24 hours at room temperature. Then filter and dry in a draft at room temperature. A 54 mg content of Crystalline Form A appears as off-white powder.

f) Suspension in tetrahydrofuran

To 80 mg of maleate prepared according to example B1 is added 0.5 ml of THF. A firm agglomerate is formed which is crushed with a spatula. The suspension obtained is stirred for 24 hours at room temperature. It is then filtered and dried in an air stream at room temperature. A 49 mg content of Crystalline Form A appears as off-white powder. Example C3: Crystallization

a) Crystallization from methanol / methylene chloride

100 mg dissolution of the maleate prepared according to

Example A1 in 1 ml methanol. After adding 14 ml of methylene chloride, a clear solution is obtained, which is allowed to stand for 5 days at 5 ° C. Then the volume is compressed to a quarter and allowed to stand again one week at 5 ° C. The solvent evaporates at room temperature completely. A content of 98 mg of crystalline Form A is obtained as an off-white powder.

b) Crystallization from toluene and acetone

A 60 mg dilution of maleate prepared according to Example A1 is prepared in 10 ml of toluene / acetone (1: 1 v / v) at 60 ° C and cooled to room temperature. The solution is allowed to stand for 4 days at 5 ° C. Then filter out and dry the bulky crystals formed. A 28 m content of Crystalline Form A is obtained as off-white crystals.

c) Crystallization from ethyl acetate

A 51 mg dilution of maleate prepared according to Example A1 in 31 ml of ethyl acetate at 65 ° C is prepared. Allow to cool to room temperature and within 2 hours needle crystals form. Allow to stand for 5 days at 5 ° C, filter and dry the crystals. A content of 33 mg of crystalline Form A is obtained as off-white, needle-shaped crystals.

d) Crystallization from tetrahydrofuran A 100 mg dilution of maleate prepared according to Example A1 is prepared in 7 ml of THF at 65 ° C and allowed to cool to room temperature. Allow to stand 4 days at 5 ° C. Then filter and dry the bulky crystals. A 28 mg content of Crystalline Form A is obtained as off-white, needle-shaped crystals.

e) Crystallization from isopropanol

2.31 g of the maleate salt prepared according to Example A6a is suspended in a 30 ml isopropanol and heated for 20 minutes at 600 rpm (revolutions per minute) at 80 ° C until a Clear solution. The amount of revolutions increases at 800 rpm and the temperature is stirred for 30 minutes, thus the amount of revolutions at the end increases to approximately 1,000 rpm. The temperature is then lowered to 65 ° C for 25 minutes and stirred at this temperature for 35 minutes. It is inoculated with 50 mg of crystalline Form A of the maleate salt and the temperature is reduced to 10 ° C during the stirring for 3 hours at a speed of 0,3 K / min. The off-white dry extract is filtered and air-dried (2.132 g, 92.3%). Only lines of Crystalline Form A according to powder X-ray Diffractogram are measured. Differential Scan Calorimetry (DSC) analysis yields endothermic signals at 165.8 ° C and 177.2 ° C. In thermogravimetric analysis no significant weight loss is observed, so that no solvated form can exist. Purity increases to 99.5% HPLC strength.

f) Crystallization from isopropanol

2.32 g of the maleate salt prepared according to Example A6a is suspended in a stirring pan in 30 ml of isopropanol and heated for 15 minutes at 600 rpm (revolutions per minute) at 80 ° C until a clear solution is formed. . The amount of revolutions increases to 800 rpm, then stirring at the mentioned temperature for 20 minutes, which causes the amount of revolutions to increase to approximately 1,000 rpm at the end. The temperature is then lowered to 65 ° C for minutes and stirred for 10 minutes. It is inoculated with 50 mg of maleate salt Crystalline Form A and reduced to temperature at 20 ° C while stirring for 3 hours at a rate of 0.25 K / min. The off-white dry extract is filtered and allowed to air dry (2.132 g, 92.3%). Only the lines of Crystalline Form A are measured according to the powder X-ray Diffractogram. In thermal analysis (DSC) endothermic signals are obtained at 163.4 ° C and 174.4 ° C. In thermogravimetric analysis no significant weight loss is observed, such that no solvated form can exist. Purity increases to 99.5% HPLC accuracy. Example C4: Crystallization by evaporation of solvents

a) Acetone / THF solvent

10 mg of maleate prepared according to Example A1 is dissolved in 15 ml of acetone / THF (1: 1, v / v) and the solvent mixture is slowly evaporated at room temperature in a stream of nitrogen to dryness. A 9 mg content of Crystalline Form A appears as an off-white powder.

b) Acetone / ethyl acetate solvent

10 mg of the maleate prepared according to Example A1 is dissolved in 15 ml of acetone / ethyl acetate (1: 1, v / v) and the solvent mixture is slowly evaporated at room temperature in a stream of nitrogen to dryness. An 8 mg content of Crystalline Form A appears as an off-white powder.

c) Methylene chloride solvent

10 mg of the maleate prepared according to Example A1 is dissolved in 15 ml of methylene chloride (1: 1, v / v) and the solvent mixture is slowly evaporated under ambient conditions in an open atmosphere at room temperature to dryness. A 9 mg content of Crystalline Form A appears as an off-white powder.

d) THF solvent / water

200 mg of maleate prepared according to Example A1 is dissolved in 4 ml

THF (1: 1, v / v) and filter the solution through a 0.22 pm filter. It is placed in a petri dish and the solvent mixture slowly evaporates under ambient conditions in an open atmosphere at room temperature until dry. A 188 mg content of Crystalline Form A appears as needle-shaped crystals.

e) THF solvent / water

200 mg of maleate prepared according to Example A1 is dissolved in 4 ml water / THF (1: 1, v / v) and the solution filtered through a 0,22 μηη filter. It is placed in a Petri dish, inoculated with Polymorph B crystals and the solvent mixture slowly evaporates under ambient conditions in an open atmosphere at room temperature until dry. After one day, needle-shaped crystals form. A content of 160 mg of Crystalline Form A appears as needle-shaped crystals.

f) THF solvent / water

200 mg of maleate prepared according to Example A1 is dissolved in 4 ml

THF (1: 1, v / v) and filter the solution through a 0.22 pm filter. It is placed in a petri dish and the solvent mixture slowly evaporates at room temperature in a stream of nitrogen until dry. After one day the needle-shaped crystals form. A 182 mg content of Crystalline Form A appears as needle-shaped crystals. ν g) 1,4-dioxane solvent

11 mg of the maleate prepared according to Example A1 is dissolved in 15 ml of 1,4-dioxane. The solution is placed in an open flask and the solvent evaporates under ambient conditions in an open atmosphere at room temperature for 4 days until dry. A 9 mg content of Crystalline Form A appears as an off-white powder.

h) SurvivorTHF

10 mg of the maleate elaborated according to Example A1 is dissolved in 15 ml of THF. The solution is placed in a petri dish and the solvent mixture slowly evaporates at room temperature under ambient conditions in an open atmosphere at room temperature for 2 days until dry. After one day the needle-shaped crystals form. A 9 mg content of Crystalline Form A appears as an off-white powder.

i) THF solvent / water

150 mg of maleate prepared according to Example A1 is dissolved in 3 ml

of THF / water (1: 1, v / v). The solvent is then evaporated at 60 ° C on a rotary evaporator. A content of 135 mg of crystalline Form A appears as an off-white powder.

j) THF solvent / water 150 mg ol maleate according to Example A1 is dissolved in 3 ml.

of THF / water (1: 1, v / v). It is then stirred at 40 ° C for 10 minutes and at 60 ° C for 1 minute. The solution is filtered through a 0.22 µm filter. It is

It is placed in a Petri dish and the solvent mixture evaporates at room temperature in a stream of nitrogen until dry. A 125 mg content of Crystalline Form A appears as an off-white powder. k) SurvivorTHF

50 mg of maleate made according to Example A1 is dissolved in 40 ml of THF at 60 ° C. It is then cooled with dry ice and allowed to reposition at -20 ° C due to turbidity. After 3 days a precipitate forms

whitish, filtering and drying. A 21 mg content of Crystalline Form A appears as an off-white powder. Example C5: Transformation of Crystalline Form B to Form A.

a) Phase equilibrium with suspension in ethyl acetate 30 mg of crystalline Form B prepared according to Example

D1 in 2 ml of ethyl acetate and stir for 18 hours at 23 ° C. Then filter and dry the residue. A 15 mg content of Crystalline Form A appears as an off-white powder.

(b) Phase equilibrium with toluene suspension 30 mg of crystalline Form B prepared according to Example

D1 in 2 ml of toluene and stir for 18 hours at 23 ° C. Then filter if the residue dries. A content of 22 mg of crystalline Form A appears as an off-white powder.

D) Preparation of Crystalline Form B

Example D1:

250 mg of maleate prepared according to Example A1 is dissolved in 5 ml

of THF / water (1: 1, v / v). The solvent mixture is then evaporated at 90 ° C in a rotary evaporator. A 208 mg content of Crystalline Form B appears as an off-white powder. Melting point rises at approximately 178 ° C, melting enthalpy rises at approximately 125 J / g, measured with DSC at a

heating speed of 10 ° C / min. The X-ray diffraction diagram is shown in Figure 3, while the Raman1 spectrum in Figure 4. Example D2:

Proceed according to Example A1, but before evaporation of the solvent, allow to stand for 22 hours. The residue is crystalline Form B. Example D3:

100 mg of the maleate elaborated according to Example A1 is dissolved in 2 ml of THF / water (1: 1, v / v). The solution is then allowed to stand for 3.5 hours at room temperature. The solvent mixture evaporates at 90 ° C in a rotary evaporator. A content of 84 mg of crystalline Form B appears as an off-white powder. Example D4:

250 mg of the maleate prepared according to Example A1 is twice dissolved in 5 ml of water / THF (1: 1, v / v). One solution is filtered through a 0.22 pm filter and the second solution through a 0.45 pm filter. Each solution is placed in a petri dish and the solvent mixture slowly evaporates under ambient conditions in an open atmosphere at room temperature. After a day spheroidal crystals are formed. After 3 days the solvent mixture is evaporated and the residues correspond to Crystalline Form B as spheroidal crystals. E \ Stability analysis

Example E1: Storage of Amorphous Form at high atmospheric humidity.

The Amorphous Form according to Example B1 is stored at room temperature with 75% environmental relative humidity and the samples examined after 2 days, 1, 2, 3, 4 and 8 weeks by Raman spectroscopy. After 2 days a mixture of crystalline forms A y Β appears. The same mix is observed also after 8 weeks. Example E2: Storage of Crystalline Form A at atmospheric humidity

high.

Maleate prepared according to Example A1 is stored at room temperature with 75% relative humidity and the samples examined after 3 days, 1, 2, 3, 4, 8 and 10 weeks by Raman spectroscopy. After 10 weeks the shows practically show no change.

Example E3: Storage of Crystalline Form B at high atmospheric humidity.

Crystalline Form B prepared according to Example D1 is stored at room temperature with 75% relative humidity and the samples examined after 3 days, 1, 2, 3, 4 and 8 weeks by Raman spectroscopy. After 8 weeks the shows practically show no changes. Example E4: Stability under particular conditions.

a) Crystalline form A under grinding.

Maleate made in accordance with Ejemplo A1 is ground in a mortar for 5 minutes. After this the crystalline Form A remains invariable. No amorphous parts are observed.

b) Crystalline form B under grinding.

Crystalline Form B according to Example D1 is ground and in a mortar for 5 minutes. After this a mixture of Crystalline Form AeB appears.

c) Crystalline form A in spray.

The maleate prepared according to Example A1 is poured into an agate ball mill (Retsch MM200 mixer mill with 5 mm agate balls) and sprayed at 20 Hz at room temperature for 180 minutes. Thereafter crystalline Form A remains invariable. No amorphous parts are observed. Example E5: Stability under pressure.

a) Crystalline form A in tablet presses

The maleate elaborated according to Example A1 is poured into a tablet press and pressed to a vacuum tablet at 100 MPa pressure for 60 minutes. After this the crystalline Form A remains invariable.

b) Crystalline form B in tablet presses.

With Crystalline Form B according to Example D1 proceed according to Example E5a). After 60 minutes a mixture of crystalline forms AeB appears.

Example E6: Water Absorption.

Water absorption is determined by dynamic absorption of water vapor (Dynamic Vapor Sorption, DVS) with DVS-1 equipment from Surface Measurement Systems Ltd. The display is placed on a platinum crucible at the tip of a microbalance. The sample is then initially equilibrated to 50% relative ambient humidity and incorporated into a measurement program for varying sample weight.

a) Amorphous Shape

The Amorphous Form has an indicated water absorption between approximately 33% ambient humidity and approximately 2.2% by weight. At higher ambient humidity, the weight decreases again, caused by a crystallization. After completion of the experiment a mixture of the crystalline forms AeB is obtained.

b) FormacristaIinaA

Crystalline Form A has a water absorption of only 0.2% of approximately 54% by weight. At the end of the measurement cycle the crystalline Form A is presented essentially without variations.

c) Crystalline form B.

Crystalline Form B has a water absorption of only about 0.2% by weight. At the end of the measurement cycle a mixture of the crystalline forms AeB is produced.

Example E7: Increased temperature stability.

The crystalline forms are stored in open and closed vessels and after a certain time, possible changes are measured as chromatographic (HPLC) as a stability parameter. Crystalline Form A shows very stable crystal form and relative chemical stability. Crystalline Form B shows very stable relative chemical stability. The results are presented in the following Table 2.

Table 2:

Polymorph Conditions HPLC Time FT Raman 'At 40 ° C / 75% RH 1 week 100.2% AA 60 ° C / 75% RH 4 weeks 100.3% AA 60 ° C (closed) 1 week 100.2% AA 60 ° C (closed) 4 weeks 100.5% AA -18 ° C (reference) 4 weeks 100% AB 40 ° C / 75% RH 1 week 100.3% AeB B 60 ° C / 75% RH 4 weeks 101, 1% AeB B 60 ° C (closed) 1 week 100.6% AeB B 60 ° C (closed) 4 weeks 100.9% AeB B -18 ° C 4 weeks 100% AeB (reference)

1 Determined crystalline form

Example E8: Water absorption of maleate and hydrochloride (Comparison).

Water absorption is determined by dynamic absorption of water vapor (Dynamic Vapor Sorption, DVS) with DVS-1 equipment from Surface Measurement Systems Ltd. The display is placed on a platinum crucible at the tip of a microbalance. The sample is then initially balanced at 50% relative ambient humidity and incorporated into a previously defined measurement program. The temperature rises to 25 ° C. The sample weight oscillation is determined after a progressive increase in humidity from 10% to 90%.

a) r + W 1 R 2 R) -3-r 2 - (dimethylamino-4-methyl- (cyclohex-1-im-phenol maleate

(Form A)

A manifest decreased water absorption of 0.06% was found. The absorbed moisture is completely distributed again in approximately 10% of

atmospheric humidity.

b) (+ V (1 R.2RV3-f2- (dimethylamino-methyl- (cyclohex-1-M-phenol-

hydrochloride (Form D)

Water absorption of approximately 2% by weight is observed by increasing relative atmospheric humidity to approximately 75%. By increasing relative atmospheric humidity to 90%, a total water absorption of approximately 5% by weight is observed. In the desorption by progressive degradation of atmospheric humidity relative to 10% more water is received than previously established, that is, a total of 8.5%. It is assumed that a variable hydrate is left. Example E9: Storage of Moisture and Dried Maleate and Hydrochloride 56/57 rH (Comparison)

The maleate and hydrochloride according to Example E8 are initially stored at 25 ° C and 75% and 95% relative atmospheric humidity for 7 days, after which time they are dried in a drying chamber at 50 ° C under vacuum. When storage begins, the DSC X-ray Diffusion (XRD) 1 patterns are determined to estimate the transition points (Tp) of dry weight (PS) and water content according to Karl-Fischer (CA) and the same. values after moisture storage and drying. X-ray diffraction patterns show no changes in AeD crystalline forms after moisture storage and drying. The starting values for the hydrochloride are Tp = 116.27 ° C, PS = 6.35% and CA = 8.00%. The output values for maleate are Tp = 170.4 ° C and 179.85 ° C, PS = 0 and CA = 0.2%. The results are shown in Table 3 (75% relative humidity) and Table 4 (95% relative humidity).

Table 3 (75%):

Salt Tp (0C) PS (%) CA (%) Tp (0C) PS (%) CA (%) Maleate 165.41 - 0.20 165.33 ~ 0.20 Hydrochloride 116.22 5.92 8.50 113.83 6.12 6.00 Table 4 (95%): Salt Tp (0C) PS (%) CA (%) Tp (0C) PS (%) CA (%) Maleate 165.92 - 0.20 165 .47 - 0.50 177.82 177.55 Hydrochloride 116.52 7.84 8.50 114.47 6.74 6.60

equipment. Methods:

Differential Scan Calorimetry (DSC): rV ^ 57/57 r ^ rJ

Perkin Elmer DSC 7 or Perkin Elmer Pyris Equipment Brand 1. Variable (heating speed) measurements on gold or aluminum crucibles.

Powder X-ray Diffraction Standard (PXRD):

The PXRDs were performed with a Philips 1710 X-ray powder diffractometer for which CuK0 radiation was used. Contrasts D were calculated from the values 2Θ, for which the wavelength is 1.54060. It is a general rule that the 2Θ values have an error rate of ± 0.1 - 0.2 °. Experimental error in contrast D values depends on the position of the line (the maximum).

Raman Spectroscopy:

The FT-Raman spectra are established with a Bruker RFS 100 FT-Raman System, which operates with an Nd: YAG Laser (1064 nm wavelength) and a liquid nitrogen cooled germanium detector. For each sample, 64 analyzes were accumulated with a resolution of 2 cm -1. Generally, an Iaser power of 100 mW is used.

Description of the Figures Figure 1 shows the X-ray diffraction pattern of the polymorph Form A. Figure 2 shows the Raman spectrum of the polymorph Form A. Figure 3 shows the X-ray diffraction pattern of the polymorph Form B. Figure 4 shows the Raman spectrum of the polymorph form B.

Claims (28)

1. "MALEIC ACID AND 3- [2- (DIMETHYLAMINO) METHYL- (CYCLOHEX-1-IL)] -Phenol salts", characterized in that they are preferably 3- [2- (dimethylamino) methyl- (cyclohex-1-yl )] - phenol maleate of formula I "Salts" according to claim 1, characterized in that it comprises the compound of formula I as a diastereomer or mixture of enantiomer diastereomers with transfiguration of the phenyl ring and the diamethylaminomethyl group (1R, 2R configuration or preferably 1S, 2S), preferably as an absolute configuration enantiomer (1R, 2R). 3. "PROCEDURE FOR PREPARING 3- [2- (DIMETHYLAMINO) METHYL (CYCLOHEX-1-yl)] - FEN OL-MALE ACT OF FORMULA I" according to claim 1, characterized in that it comprises the grouping of components and 3. - [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol and maleic acid, for which one of the components is preferably present in diluted or suspended form. 4. "PROCEDURE AS IN CLAIM 3 FOR PREPARING 3- [2- (DIMETHYLAMINE) METHYL- (CYCLOHEX-1-IL)] - FEN OL-M ALEATE OF FORMULA I", as claimed in claim 1, comprising the following steps: : a) Dilution of 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] -phenol in a <formula> formula see original document page 59 </formula> b) Mixing of the solution with maleic acid or a maleic acid solution, and (c) isolation of the compound of formula I, for which preferably in no stage of the procedure does the temperature exceed 100 ° C. 5. "MALEIC ACID AND SALT 3- [2- (D-METHYLAMINO) METHYL (CYCLOHEX-1-IL)] PHENOL" characterized in that it comprises a procedure according to claim 3 or 4. 6. "CRYSTALLINE SHAPE OF COMPOSITE 3- [2- (DIMETHYLAMINO) METHYL- (CYCLOHEX-1-IL)] - FE NOL-M ALEATE OF FORMULA I" according to claim 1, characterized in that it has a ray diffraction pattern Characteristic X between 2 ° and 35 ° 2Θ with pronounced characteristic lines, expressed as d (A) values: 9.4 (vs); 6.8 (m); 5.56 (s); 5.30 (s); 5.22 (s); 4.71 (s); 4.66 (s); 4.24 (m); 4.12 (m); 4.03 (m); 3.98 (s); 3.76 (m); 3.27 (m) .. 7. "CRYSTALLINE FORM OF COMPOSITE 3- [2- (DIMETHYLAMINO) METHYL (CYCLOHEX-1-IL)] - FE NOL-M ALE ACT OF FORMULA I" according to claim 1, characterized by a powder diffractogram understand one or more of the following reflections: 9,38; 9.94 and 10.35 (respectively ± 0.5 in 2Θ). 8. "Crystalline form according to Claim 7", characterized in that the x-ray diagram in powders further provides one or more of the following reflections: 12,76; 15.94; 17.54; 19.28; 28.68 and 31.99 (respectively ± 0.2 in 2Θ). 9. "CRYSTALLINE FORM OF COMPOSITE 3- [2- (DIMETHYLAMINE) METHYL (CYCLOHEX-1-IL)] - PHENOL-MALEATE OF FORMULA I" according to claim 1, characterized in that a Raman spectrum comprises one or more more of the following bands, expressed respectively in amount of waves (cm -1): 118 (vs), 188 (w), 400 (w), 676 (w), 2812 (w), 2879 (m), preferably a or more of the following bands: 118 (vs), 118 (w), 292 (m), 328 (m), 359 (w), 400 (w), 486 (vw), 676 (w), 901 (w) , 1025 (w), 1273 (m), 1351 (m), 1412 (w), 1569 (vw), 1601 (m), 2812 (w), 2879 (m), 2986 (m), 3060 (m) . 10. "CRYSTALLINE A FORM OF COMPOSITE 3- [2- (DIMETHYLAMINO) METHYL (CYCLOHEX-1-yl)] - PHENOL-MALEATE OF FORMULA I" according to claim 1, characterized in that it has an X-ray diffraction pattern as in Figure 1. 11. "CRYSTALLINE A FORM OF COMPOSITE 3- [2- (DIMETHYLAMINE) METHYL (CYCLOHEX-1-IL)] - L-MALEATE HAY OF FORMULA I" according to claim 1, characterized in that it has a Raman spectrum as in Figure 2. 12. "PROCEDURE FOR DEVELOPING THE CRYSTALLINE FORM OF COMPOSITE 3- [2- (DIMETHYLAMINE) METHYL- (CYCLOHEX-1-IL)] - PHENOLMALEATE OF FORMULA I" according to one or more of claims 6-11, characterized in that: (a) It comprises a solid, amorphous, 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate powder form with an inert gas containing water vapor; or (b) A suspension of 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate Amorphous Suspension is prepared in a solvent as a base and stirred until complete formation of Crystalline Form A; or (c) 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate are diluted in a solvent and then precipitated; or Mix 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] -phenol with maleic acid, for which preferably one of these as a minimum is in dilute or suspended form, and is isolated. the product obtained, provided that the temperature does not exceed 100 ° C. 13. "CRYSTALLINE FORM A OF COMPOSITE 3- [2- (DIMETHYLAMINO) METHYL (CYCLOHEX-1-yl)] - PHENOL-MALEATE OF FORMULA I" according to claim 1, according to a procedure according to Claim 12. "CRYSTALLINE FORM A" according to one or more of claims 6-11 and 13, characterized in that there is 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate in the configuration. (1R.2R). 15. "3- [2- (DIMETHYLAMINE) METHYL- (CYCLOHEX-1-IL)] - PHENOL-MALEATE FORMULA B" CRYSTALLINE B FORM ", characterized by a characteristic X-ray diffraction pattern from 2 ° to 35 ° 2Θ with manifest characteristic lines, expressed in d (A) values: 10,6 (m); 1.5 (m); 7.3 (m); 6.1 (s); 5.29 (s); 4.88 (m); 4.72 (m); 4.47 (vs); 4.43 (m); 4.26 (m); 4.24 (m); 3.99 (s); 3.71 (m); 3.52 (m); 3.30 (s). 16. "3- [2- (DIMETHYLAMINO) METHYL- (CYCLOHEX-1-IL)] - PHENOL-MALEATE FORMULA B" CRYSTALLINE B SHAPE according to claim 1, characterized by an X-ray diffraction diagram in powders comprising one or more of the following reflections: 8.36; 14.5 and 14.83 (respectively ± 0.5 in 2Θ). A "CRYSTALINE SHAPE B" according to claim 16, characterized in that the χ ray diffraction diagram in powders further presents one or more of the following reflections; 11.85; 12.18; 18.16; 22.85; 29.1 and 29.41 (respectively ± 0.2 in 2Θ). 18. "Crystalline form A of the 3- [2- (dimethylamino) methyl-cyclohex-1-yl] -phenol malate of formula I" according to claim 1, characterized in that through a Raman spectrum comprises one or more more of the following bands, expressed respectively in wave numbers (cm -1): 229 (m), 875 (m) and 2829 (m), preferably one or more of the following bands: 229 (m), 307 (ww) , 372 (w), 605 (vw), 875 (m), 890 (w), 1010 (w), 1197 (m), 1401 (vw), 1480 (vw), 1583 (m), 1703 (s) , 2829 (m), 2953 (s). 19. "CRYSTALLINE B FORM OF COMPOSITE 3- [2- (DIMETHYLAMINE) METHYL (CYCLOHEX-1-yl)] - PHENOL-MALEATE OF FORMULA I" according to claim 1, characterized in that it has an X-ray diffraction pattern as shown in Figure 3. 20. "CRYSTALLIN B-form of the compound 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate of formula I" according to claim 1, characterized in that it has a Raman spectrum as shown in Figure 4 "PROCEDURE FOR PREPARING CRYSTALLINE B FORM OF 3- [2- (DIMETHYLAMINE) METHYL- (CYCLOHEX-1-yl)] - PHENOLMALEATE", according to one or more of claims 15-20, characterized in that it dissolves the 3- [2- (dimethylamino) methyl- (cyclohex-1-ii)] -phenol maleate compound in a mixture of tetrahydrofuran and water with a water content of 0.8: 1.2 to 1.2: 0.8 , and then the solvent mixture is completely removed (a) at a minimum temperature of 80 ° C, or (b) at room temperature in an open container in an open atmosphere in contact with ambient humidity, or (c) stirring. a suspension of 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate in a solvent as a base at a minimum temperature of 120 ° C until complete formation of crystalline Form B. 22. "CRYSTALLINE B FORM OF COMPOUND 3- [2- (DIMETHYLAMINO) METHYL (CYCLOHEX-1-yl)] - PHENOL-MALEATE OF FORMULA I" according to claim 1, characterized in that it is obtained from a procedure according to claim 21. "CRYSTALLINE FORM B" according to one or more of Claims 15-20 and 22, characterized in that the 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate is in the configuration. (1R, 2R) .. 24. "PHARMACEUTICAL COMPOSITION", characterized in that it comprises an effective dose of 3- [2- (dimethylamino) methyl- (cyclohex-1-yl)] phenol maleate of formula I as claimed in claim 1 and a pharmaceutical carrier or a diluent. pharmaceutical. "COMPOSITION" according to claim 24, characterized in that the compound of formula I is crystalline form A, crystalline form B or a mixture of forms AeB. "Composition" according to Claim 25, characterized in that the compound of formula I is contained as Crystalline Form A. 27. "USE OF 3- [2- (DIMETHYLAMINO) METHYL- (CYCLOHEX-1-IL)] - PHENOL-MALEATE COMPOUND I", characterized in that it is employed in the preparation of a pharmaceutical composition, in particular for the treatment of of pain conditions. 28. "PAIN PROCESSING PROCEDURE", characterized in that a patient in pain is administered an effective dose of the compound 3- [2- (dimethylamino) methyl · (cyclohex-1-yl)] phenol maleate. formula I.